Exciting research is laying the groundwork to develop a promising new targeted therapy for aggressive subtypes of childhood leukaemia including infant acute lymphoblastic leukaemia (ALL).

Lead investigator, Dr Michelle Henderson is a senior scientist, project leader and joint Research Manager of Molecular Diagnostics at Sydney’s Children’s Cancer Institute.

Before moving to the Children’s Cancer Institute, Dr Henderson spent 10 years working on the genetics and molecular biology of breast cancers at the Garvan Institute of Medical Research.

“Fourteen years ago, the opportunity to move to the Children’s Cancer Institute came up,” explained Dr Henderson.

“After spending years studying individual genes involved in cancer, I wanted to take a step closer to the clinic where I could potentially discover new treatments and have a more direct impact on people with cancer.”

While major research advancements have significantly improved survival rates in childhood leukaemia, Dr Henderson and her team are working to target certain subtypes of childhood leukaemia that still have very poor prognoses.

These include children who fail induction treatment, relapse during treatment or whose leukaemia harbours chromosomal rearrangement of the Mixed Lineage Leukaemia (MLL) gene*, an abnormality that occurs in 90% of infant ALL, with a survival rate of less than 50%.

“It can be an extra challenge with children as their bodies are still developing and these chemotherapeutic agents that work so well for leukaemia can still be very harmful to the patient,” said Dr Henderson.

“If it’s a more aggressive cancer then that child will receive more aggressive treatment and that can affect them later in life, leading to physical problems such as heart disease, osteoporosis, infertility, obesity, or even the risk of a second cancer.

“This presents an urgent need for the development of novel treatment strategies incorporating more selective, targeted therapies, allowing for a reduction in chemotherapy dosage and toxicity.”

For the past 10 years, Dr Henderson’s lab has collaborated with a lab in Buffalo, New York, conducting ‘screens’ with the aim of finding new drugs which specifically kill cancer cells without affecting normal cells.

Together they have discovered a new drug, OT-82, which has ‘remarkable’ potential to improve treatment in aggressive childhood leukaemia.

Dr Henderson’s research was awarded a Priority-driven Collaborative Cancer Research Scheme (PdCCRS) grant in 2019 to further develop this therapy.

This grant was co-funded by the Leukaemia Foundation, The Kid’s Cancer Project and Cancer Australia.

“This drug, OT-82, blocks the production of a cellular biochemical called nicotinamide adenine dinucleotide (NAD) which rapidly dividing cancer cells can be dependent on for energy,” said Dr Henderson.

“NAD is also a co-factor for a number of enzymes that help the cell repair itself and so leukaemia cells can require a lot of it because they’re continually growing and need to repair themselves all the time.

“Based on the knowledge that cancer cells depend on NAD more than normal cells, researchers have tried for many years to design a compound that actively targets and inhibits production of NAD. But a suitable compound was yet to be found.”

Although not looking to target this pathway in particular, Dr Henderson and her collaborators in the U.S. came upon such a compound through a screening strategy aimed directly at blood cancer cells.

“We were surprised when the compound that came out of the search appeared to be an inhibitor of an enzyme called NAMPT (nicotinamide phosphoribosyltransferase), which is necessary for producing NAD in the cell but whose association with blood cancers was unknown,” she explained.

“This particular compound universally kills blood cancer cells, but the normal blood cells just go into a pause.

“The normal blood cells don’t die, they are just in pause and then when you stop treating them, they rejuvenate again, whereas the cancer cells don’t.

“It’s interesting that we’ve come across it through a completely blind approach of just screening thousands and thousands of compounds and found one that targets blood cancer cells.

“This compound seems to be very well tolerated so far in adult trials and is earmarked for going further into paediatric trials.”

With this grant, Dr Henderson and her team are laying the groundwork for these paediatric trials, by determining which children could be most responsive.

“Part of our research is to determine exactly which subtypes of leukemia will respond, both on a broad, phenotype level, and at a molecular level, to find which genes are expressed in that particular cancer,” said Dr Henderson.

“We want to have a set of biomarkers, or subtype markers, that say if a patient has this cancer and it expresses this gene or mutation, they are more likely to respond to OT-82.

“So far, we have found a set of very responsive patient samples that each have mutations in DNA repair genes.

“We think that when they have a weakness in their DNA repair, with the cancer cell having to grow so rapidly and requiring NAD for repair, that’s when they are particularly responsive to OT-82.

“We are also looking at how OT-82 can be used in combination therapy to promote the response to other drugs currently being used for leukaemia treatment.”

The impact of this project is further enhanced by a collaborative grant recently awarded to the Children’s Cancer Institute to deliver personalised medicine to every child in Australia.

“It’s going to become a reality that across the country every child’s cancer will be sequenced,” said Dr Henderson.

“Such a completely individualised approach to treatment means that OT-82 could have an incredible impact on patient survival outcomes.”

Inhibiting NAD also appears to be relevant to some other cancers that depend on the same pathway.

“They might be solid tumours like sarcoma or brain tumours with certain genetic mutations you can screen for that cause dependence on this particular pathway,” said Dr Henderson.

The next big challenge for the research team will be gearing up for a paediatric leukaemia clinical trial.

“That’s why this funding from the Leukemia Foundation, The Kid’s Cancer Project and Cancer Australia is so important,” said Dr Henderson.

“Even though a relatively small number of children may have these high-risk leukaemia subtypes, it will have a significant impact on survival outcomes for this group and may be applied across other cancer types.

“The whole team is so thankful to have the opportunity to gather this supporting evidence and make a real case for OT-82 to be taken to clinical trial stage for these deadly childhood leukaemias.”

*Also referred to as Mixed Lineage Leukaemia Gene Rearrangement (MLL-r). This occurs when a piece of DNA is swapped with another chromosome which results in two different genes being abnormally joined together. The resulting protein can no longer control the development of the blood system and blood cells grow out of control, resulting in leukaemia.